ORGANIC LETTERS
Cycloaddition Reactions of Alkoxy Alkynyl Fischer Carbene Complexes with o-Quinodimethanes (oQDMs)
2002 Vol. 4, No. 21 3659-3662
Jose´ Barluenga,* Manuel A. Ferna´ndez-Rodrı´guez, and Enrique Aguilar Instituto UniVersitario de Quı´mica Organometa´ lica “Enrique Moles”, Unidad Asociada al C.S.I.C., UniVersidad de OViedo, C/Julia´ n ClaVerı´a, 8, 33006 OViedo, Spain
[email protected] Received July 24, 2002
ABSTRACT
The reaction of o-quinodimethanes (oQDMs) with alkoxy alkynyl Fischer carbene complexes is highly dependent on the carbene complex. Thus, for arylalkynyl carbene complexes, the initial [4 + 2]-cycloadduct evolves opening a new entry to the benzo[b]fluorene skeleton, which is present in many natural products. However, for alkenylalkynyl carbene complexes, the reaction takes place through the double bond, instead of the triple bond, in an unprecedented fashion, leading to new functionalized alkynyl carbene complexes.
Cycloaddition reactions between 1,3-dienes and R,β-acetylenic Fischer carbene complexes have been extensively developed.1 In these reactions, the initial [4 + 2] cycloadducts (which are, in fact, cyclohexenylcarbenes) can evolve, spontaneously or by warming, to form cyclopentadienes by a cyclopentannulation reaction, when the alkyne is substituted by an aryl2 or an alkenyl3 group. However, the o-quinodimethane (oQDM, o-xylylene) system has remained elusive as a dienic antagonist of Fischer carbene complexes; this is probably due to the lack of (1) For recent reviews regarding the reactivity of Fischer alkynyl carbene complexes, see: (a) Aumann, R.; Nienaber, H. AdV. Organomet. Chem. 1997, 41, 163-242. (b) De Meijere, A.; Schirmer, H.; Duetsch, M. Angew. Chem., Int. Ed. 2000, 39, 3964-4002. (2) (a) Barluenga, J.; Aznar, F.; Barluenga, S. Chem. Commun. 1995, 1973-1974. For related transformations, see: (b) Barluenga, J.; Toma´s, M.; Ballesteros, A.; Santamarı´a, J.; Sua´rez-Sobrino, A. J. Org. Chem. 1997, 62, 9229-9235. (c) Barluenga, J.; Lo´pez, L. A.; Martı´nez, S.; Toma´s, M. Synlett 1999, 219-221. (d) Palomero, M. A. Ph.D. Dissertation, Universidad de Oviedo, Oviedo, Spain, 2002, pp 66-68. (3) (a) Barluenga, J.; Aznar, F.; Barluenga, S.; Martı´n, A.; Garcı´a-Granda, S.; Martı´n, E. Synlett 1998, 473-474. (b) Barluenga, J.; Aznar, F.; Barluenga, S.; Ferna´ndez, M.; Martı´n, A.; Garcı´a-Granda, S.; Pin˜era-Nicola´s, A. Chem. Eur. J. 1998, 4, 2280-2298. 10.1021/ol026600f CCC: $22.00 Published on Web 09/17/2002
© 2002 American Chemical Society
methodologies for synthesizing oQDM derivatives that are compatible with carbene complexes.4 The reversible conrotatory opening of the cyclobutene ring in benzocyclobutenes has been a widely used procedure for the generation of oQDM derivatives, although high temperatures are usually required.5 However, it is known that electron-donatingsubstituted benzocyclobutenes exhibit outward opening even at temperatures below 0 °C. Also, very recently, Danishefsky has reported that trans-1,2-bis(trialkylsilyloxy)benzocyclobutenes can partake in intermolecular Diels-Alder cycloadditions with suitable carbodienophiles6 and heterodienophiles7under remarkably mild conditions. In this regard, we have also prepared highly functionalized trans- and cis-1,2(4) For reviews regarding oQDMs chemistry, see: (a) Martı´n, N.; Seoane, C.; Hanack, M. Org. Prep. Proced. Int. 1991, 23, 237-272. (b) Chou, T. ReV. Heteroatom Chem. 1993, 8, 65-104. (c) Segura, J. L.; Martı´n, N. Chem. ReV. 1999, 99, 3199-3246. (5) For recent reviews regarding benzocyclobutenes, see: (a) Michellys, P. Y.; Pellisier, H.; Santelli, M. Org. Prep. Proced. Int. 1996, 28, 545. (b) Mehta, G.; Cota, S. Tetrahedron 2001, 57, 625-659. (6) (a) Allen, J. G.; Hentemann, M. F.; Danishefsky, S. J. J. Am. Chem. Soc. 2000, 122, 571-575. (b) Allen, J. G.; Danishefsky, S. J. J. Am. Chem. Soc. 2001, 123, 351-352.
bis(trialkylsilyloxy)benzocyclobutenes from Fischer carbene complexes and isocyanides8 that can participate in intermolecular Diels-Alder reactions. The benzo[b]fluorene tetracyclic nucleus is present in several naturally occurring compounds that display antibiotic properties (Figure 1). Biosynthetic studies have proved that
Figure 1. Naturally occurring compounds bearing the benzo[b]fluorene skeleton.
kinobscurinone is an intermediate9 for both kinamycins and stealthins. Besides being strongly active against Grampositive bacteria,10 some kinamycins, as well as structurally related LomaiViticin A,11 also have shown antitumor activity. Stealthins, on their hand, exhibit a potent free radical scavenger activity, which makes them potentially amenable for the treatment of diseases caused by oxygen-derived free radicals such as atherosclerosis or Parkinson’s disease.12 We hypothesized that the thermal reaction between oQDMs and R,β-acetylenic Fischer carbene complexes may follow a tandem [4 + 2]-cycloaddition/cyclopentannulation sequence leading to complex polycyclic structures. In this letter, we present the results we have obtained in this area. Danishefsky’s benzocyclobutenes 16 were initially treated with alkoxy arylalkynyl Fischer carbene complexes 2 in benzene or toluene at 45 °C. The reaction was monitored by TLC until the disappearance of the carbene spot (3-7 (7) Hentemann, M. F.; Allen, J. G.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2000, 39, 1937-1940. (8) (a) Barluenga, J.; Aznar, F.; Palomero, M. A. Chem. Eur. J. 2002, 8, in press. (b) However, the oQDM precursors prepared in ref 8a do not react with alkoxy alkynyl Fischer carbene complexes: Barluenga, J.; Aznar, F.; Palomero, M. A. Unpublished results. (9) Gould, S. J. Chem. ReV. 1997, 97, 2499-2509. (10) (a) Omura, S.; Nakagawa, A.; Yamada, H.; Hata, T.; Furusaki, A.; Watanabe, T. Chem. Pharm. Bull. 1971, 19, 2428-2430. (b) Isshiki, K.; Sawa, T.; Nagawaga, H.; Matsuda, N.; Hattori, S.; Hamada, M.; Takeuchi, T. J. Antibiot. 1989, 42, 467-469. (c) Arya, D. P.; Jebaratnam, D. J. J. Org. Chem. 1995, 60, 3268-3269. (11) Laufer, R. S.; Dmitrienko, G. I. J. Am. Chem. Soc. 2002, 124, 18541855. (12) (a) Shin-ya, K.; Furihata, K.; Teshima, Y.; Hayakawa, Y.; Seto, H. Tetrahedron Lett. 1992, 33, 7025-7028. (b) Koyama, H.; Kamikawa, T. J. Chem. Soc., Perkin Trans. 1 1998, 203-209. 3660
h). After workup, dihydrobenzo[b]fluorenes 3 and benzo[b]fluorenes 4 were isolated in the yields listed in Table 1.
Table 1. Cycloaddition Reactions of Alkoxy Arylethynylcarbenes 2 with Benzocyclobutene 1-Derived OQDMs
entry
1
Si*
2
M
R
3
yielda
4
yielda
1 2 3 4
1a 1b 1a 1a
TBS TMS TBS TBS
2a 2a 2b 2c
Cr Cr W Cr
H H H OMe
3a 3b 3a 3c
73 9 35 65
4a 4b 4a 4c
25 80 55 5
a
Isolated yield after chromatography based on starting carbene 2.
Some conclusions can be extracted from analysis of Table 1. The reaction takes place with either chromium or tungsten carbene complexes in high combined yields although, in the latter case, the reaction is slower (7 h) and silanol elimination is favored leading to 4a as the major product. When silyloxybenzocyclobutenes 1a are warmed together with chromium carbene complexes, it is possible to exert control over the reaction, as the sole products detected by TLC and 300 MHz 1H NMR in the crude residue are dihydrobenzo[b]fluorenes 3. However, partial silanol elimination occurs during column chromatrography purification thus originating benzo[b]fluorenes 4, while compounds 3 are still isolated as the main products. Silanol elimination also takes place very easily during the workup when the oQDM is generated from TMS-oxybenzocyclobutene 1b, even when reacted with chromium carbene complexes (Table 1, entry 2). The scope of the reaction was examined by treating benzocyclobutene 1a with sterically hindered alkoxy carbene 5, amino carbene 6, or methyl 3-phenylpropionate 7. However, in the conditions described before or in refluxing benzene, 1a does not react with any of those substrates; it dimerizes instead to form 8. The last case is one more example that corroborates the fact that metal carbenesubstituted alkynes are better dienophiles than the analogous esters. The proposed mechanism is initiated by a thermally driven conrotatory ring opening of benzocyclobutenes 1 to generate the corresponding oQDMs smoothly, which would react in a [4 + 2] fashion with Fischer alkynyl carbene complexes 2, to form cycloadducts I, which were not detected. A nucleophilic attack of the aryl ring on the carbene carbon of Org. Lett., Vol. 4, No. 21, 2002
I, as was proposed by Aumann for the cyclopentannulation reactions of metallatrienes,3b,13 would lead to intermediate II, which suffers elimination of the metallic fragment to produce III. A 1,5-hydrogen sigmatropic rearrangement promoted by the rearomatization of the aryl ring leads to the formation of compounds 3. Finally, in situ or silica gelcatalyzed trialkylsilanol elimination accounts for the obtainment of benzo[b]fluorenes 4. The elucidation of the structure of the cycloadducts was achieved by the usual techniques (COSY, HMQC, HMBC). NOESY experiments (400 MHz) served to ascertain the regiochemistry of the silanol elimination when benzo[b]fluorenes 4 are formed (NOESY performed on 4a) and the relative configuration for dihydrobenzo[b]fluorenes 3 (NOESY performed on 3c), which was found to be trans between the methoxy and both silyloxy groups, as depicted above and as expected for steric reasons. We treated next benzocyclobutenes 1 with alkenylsubstituted alkynyl chromium carbene complexes 9, bearing in mind that these reactions should proceed by a tandem double cycloaddition-cyclopentannulation.3b However, to our surprise, carbene complexes 9 reacted with oQDMs in a Diels-Alder fashion through the double bond, instead of the triple bond, producing new tetrahydronaphthylalkynyl chromium carbene complexes 12. This result was totally unexpected as, prior to our experiments, carbene complexes 9 had only shown this behavior in one case, leading to the corresponding [4 + 2]-cycloadduct as the minor product.3b Similarly, tetrahydronaphthylalkynyl tungsten carbene com-
Table 2. [4 + 2]-Cycloaddition Reactions of Alkoxy Alkenylethynylcarbenes 9 and Ester 10 with Benzocyclobutene 1-Derived OQDM78s
Figure 2.
plex 13 was obtained when tungsten carbene complex 10 was heated in the presence of 1a. Carbene complexes 12 (13) were isolated in good yields (Table 2) as single diastereomers, with the exception of carbene 12d for which a 4:1 diastereomeric mixture was observed. Again, the reaction was tested with the analogous ester 11. In this case, only less than a 10% of cycloaddition product 14c could be estimated as a mixture of diastereomers by 1H NMR (300 MHz) of the crude residue after 3 days of warming at 45 °C. Presumably, the lesser reactivity of the ester 11 as dienophile and the rapid dimerization of the oQDM, as pointed out before, account for this low amount of cycloadduct. Compounds 12 (13) gave spectroscopically consistent data, and their relative configuration was assigned to be the one depicted above by NOESY correlations (400 MHz). In most cases, the only compound detected was the diastereomer that comes from an exo-selective approach of the double bond of carbenes 9 (10) to the oQMDs (Figure 3a). However, for carbene 12d the major diastereomer observed was the result of the endo-selective approach (Figure 3b).
Figure 3. (a) Preferred exo-selective transition state for the cycloaddition reaction of oQDMs and carbene complexes 9a-c and 10. (b) Preferred endo-selective transition state for the cycloaddition reaction with carbene complex 9d.
entry
1
dienophile
1 2 3 4 5 6 7
1a 1a 1a 1a 1b 1a 1a
9a 9b 9c 9d 9b 10 11
R1
R2
Me Ph -(CH2)3-(CH2)4H Ph -(CH2)3-(CH2)4Me Ph
time
product
yielda
2h 3h 3h 2h 2h 3h 3 days
12a 12b 12c 12d 12e 13 14c
70 95 78 80b 50 86
